B-cell non-Hodgkin's lymphomas are known to express BCL-2 family proteins, of which the myeloid cell leukemia-1 (MCL-1) protein is a member. MCL-1 is involved in viability and immortalization of normal and neoplastic B cells, and expression is regulated transcriptionally and posttranscriptionally, resulting in an anti-apoptotic (full length) or a pro-apoptotic (short isoform) gene product. In this study, we assessed 151 B-cell lymphomas for MCL-1 expression and analyzed for expression of the full-length and short isoforms of MCL-1 in B-cell lymphoma cell lines. By using immunohistochemistry, a subset of neoplasms in 9 lymphoma types studied expressed MCL-1, but expression was more frequent and intense in high-grade (43 of 49, 88%) compared with low-grade (34 of 92, 37%) lymphomas (P < 0.0001). In follicular lymphomas, MCL-1 expression positively correlated with increasing grade; 1 (14%) of eight grade 1, 7 (70%) of ten grade 2, and all 9 (100%) grade 3 were positive (P < 0.0008). All plasma cell myeloma cases assessed were also MCL-1 positive. By using Western blot analysis, 6 of 7 high-grade B-cell lymphoma cell lines showed predominant expression of full-length MCL-1, compared with no or weak expression of the short isoform. One myeloma and 1 of 2 mantle cell lymphoma cell lines also tested showed only full-length isoform expression. Our data suggest that MCL-1 is frequently expressed in high-grade B-cell lymphomas and plasma cell myeloma, most likely in its full-length isoform that is an active anti-apoptotic gene product. MCL-1 expression also correlates with grade and may contribute to transformation in follicular lymphomas.